DE19755800A1 - Cyclopeptide derivatives - Google Patents

Abstract

The invention relates to compounds of formula (I), R-Q-X, wherein R = cyclo-(Arg-Gly-Asp-Z), whereby Z is bonded in a side chain to Q or to Z if Q is lacking, Q is lacking and represents -[CO-R<1>-NH-X]m, -[NH-R<1>-CO-]m, -[CO-R<1>-CO-]m, -(CO-CH2-O-CH2CH2-O-CH2CH2-NH-)n, -(NH-CH2-O-CH2CH2-O-CH2CH2-CO-)n, -(NH-CH2CH2-O-CH2CH2-O-CH2-CO-)n or -(CO-CH2-O-CH2CH2-O-CH2-CH2-NH-)n-[CO-R<1>-NH-]m, X = -CO-CH=CH2, -CO-C(CH3) = CH2, -NH-CH = CH2, -NH-C(CH3)=CH2 or -NH-(CH2)p-SH, Z means, independently from each other, an amino acid radical or a dipeptide or tripeptide radical, whereby the amino acids, independently from each other, are selected from a group consisting of Ala, Asn, Asp, ARg, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val or M, whereby the above-mentioned amino acids can also be derivatized, and the amino acid radicals are linked to each other like peptides by the alpha amino and alpha carboxy groups, and whereby m is always contained, M = NH(R<8>)-CH(R<3>)-COOH, and R<1>, R<3>, R<8>, m, n and p have the meanings cited in claim 1, in addition to the salts thereof, whereby said substances can be used as integrin inhibitors, especially in the treatment of implant-induced diseases, defects, inflammations and osteolytic diseases such as osteoporosis, thrombosis, cardiac infarction, and arteriosclerosis, in addition to accelerating and amplifying the integration process of an implant or biocompatible surface in tissues.

Description

The invention relates to compounds of the formula I.

RQX I

wherein
R cyclo- (Arg-Gly-Asp-Z), where Z is attached to Q in the side chain or, if Q is absent, to X,
Q is missing, - [CO-R ¹ -NH-] _m , - [NH-R ¹ -CO-] _m , - [CO-R ¹ -CO-] _m , - (CO-CH ₂ -O-CH ₂ CH ₂ -O-CH ₂ CH ₂ -NH-) _n , - (NH-CH ₂ -O-CH ₂ CH ₂ -O-CH ₂ CH ₂ -CO-) _n or - (CO-CH ₂ -O- CH ₂ CH ₂ -O-CH ₂ CH ₂ -NH-) _n - [CO-R ¹ -NH-] _m ,
X -CO-CH = CH ₂ , -CO-C (CH ₃ ) = CH ₂ , -NH-CH = CH ₂ , -NH-C (CH ₃ ) = CH ₂ or -NH- (CH ₂ ) _p - SR ¹⁰ ,
Z each independently of one another an amino acid residue or a di- or tripeptide residue, the amino acids being selected independently of one another from a group consisting of Ala, Asn, Asp, Arg, Cys, Gln, Glu, Gly, His, Homo-Phe, Ile, Leu , Lys, Met, Phe, Phg, Pro, Ser, Thr, Trp, Tyr, Val or M,
wherein the amino acids mentioned can also be derivatized, and the amino acid residues are linked to one another in peptide fashion via the α-amino and α-carboxy groups, and
where M is always included,
M NH (R ⁸ ) -CH (R ³ ) -COOH,
R ¹ is absent or R ² , R ⁹ , R ² -R ⁹ -R ² , unsubstituted or mono- or disubstituted by R ⁵ phenylene, the chain length of R ^{5 being} independent of each other,
R ² alkylene with 1-10 C atoms, where 1 or 2 methylene groups can be replaced by S, -CH = CH- or -C∼C-,
R ³ -R ⁵ -R ⁴ , -R ⁶ -R ⁴ , -R ⁷ -R ⁴ ,
R ⁴ OH, NH ₂ , SH or COOH,
R ⁵ alkylene with 1-6 C atoms,
R ⁶ alkylene phenylene with 7-14 C atoms,
R ⁷ alkylenephenylalkylene with 8-15 C atoms,
R ^{8 is} H, A or alkylenephenyl with 7-12 C atoms,
R ⁹ cycloalkylene with 3-7 C atoms,
R ¹⁰ H or an S protective group,
A alkyl with 1-6 C atoms,
Hal F, Cl, Br or I,
m, n each independently of one another 0, 1, 2 or 3 and
p is 1, 2 or 3,
where, as far as residues of optically active amino acids and amino acid derivatives are concerned, both the D and L forms are included,
as well as their salts.

Similar compounds of cyclic peptides are from DE 43 10 643 and DE 195 38 741 known.

The compound cyclo- (Arg-Gly-Asp-Glu (ε-Ahx-Cys-NH ₂ ) -D-Val) is from D.Delforge et al. from Anal. Biochem. 242, 180-186 (1996).

The invention was based on the object, new compounds with valuable len properties to find, especially those that are used to manufacture of drugs can be used.

It has been found that the compounds of the formula I and their salts have very valuable pharmacological properties with good tolerability. Above all, they act as integrin inhibitors, in particular inhibiting the interactions of the α _V -, β ₃ or β ₅ integrin receptors with ligands, such as, for. B. the binding of fibrinogen to the β ₃ integrin receptor. The compounds are particularly effective in the case of the integrins α _V β ₃ , α _V β ₃ α _IIb β ₃ and α _V β ₁ , α _V β ₆ and α _V β ₈ .

This effect can e.g. B. can be detected by the method that by J.W. Smith et al. in J. Biol. Chem. 265, 12267-12271 (1990) is described.

The dependence of the development of angiogenesis on the change effect between vascular integrins and extracellular matrix protein is from P.C. Brooks, R.A. Clark and D.A. Cheresh in Science 264, 569-71 (1994).

The possibility of inhibiting this interaction and thus to Initiation of apoptosis (programmed cell death) angiogenic vascular Cells by a cyclic peptide is from P.C. Brooks, A.M. Montgomery, M. Rosenfeld, R.A. Reisfeld, T.-Hu, G. Klier and D.A. Cheresh in Cell 79 1157-64 (1994).

Compounds of formula I, the interaction of Integrinrezep gates and ligands, such as. B. from fibrinogen to the fibrinogen receptor (Glycoprotein IIb / IIIa) block, prevent as GPIIb / IIIa antagonists the spread of tumor cells through metastasis. This is through the following observations confirm:  

The spread of tumor cells from a local tumor into that vascular system occurs through the formation of micro-aggregates (micro thrombi) by interaction of the tumor cells with platelets. The Tumor cells are shielded and protected by the micro-aggregate are not recognized by the cells of the immune system.

The micro-aggregates can stick to the walls of the vessel, causing further penetration of tumor cells into the tissue is facilitated. Since the formation of the microthrombi by fibrinogen binding to the fibrino gene receptors mediated on activated platelets can GPIIa / IIIb antagonists regarded as effective metastasis inhibitors become.

The (meth) acrylate residue serves to covalently attach the peptides to biocompatible Surfaces of e.g. B. implants to bind the free acrylic or Have methacrylate residues, such as. B. molded polymethyl methacrylate (Bone cements) or layers containing acrylate or methacrylate e.g. B. on metal surfaces.

Correspondingly, the thiol residue serves for peptide attachment. B. Goldober surfaces.

The invention therefore relates in particular to the compounds of Formula I for covalent bonding via the functional group of the rest X on biocompatible surfaces.

In the case of X = -NH- (CH ₂ ) _p -SR ¹⁰ , the functional group that binds to the surface is the SH residue, i.e. when R ¹⁰ = H.

The peptides according to the invention now enable biofunctionalization of biomaterials, especially implants for all conceivable organs by coating them, the adhesion predominantly of those cell species that stimulate tissue integration of the corresponding biomaterial. With the use such coatings is an accelerated and the reinforced int Gration of various biomaterials / implants with improved long-term to achieve stability after their introduction into the body.  

It is in this context on the same day from the Applicant filed second application referred in the appropriate Biomaterials and the coating thereof with the Invention appropriate connections are described.

The peptides according to the invention bind selectively to integrins. After immobilization on biocompatible surfaces, e.g. B. implants, they stimulate the adhesion of cells that carry integrins. After coating the compounds on the surfaces, those cell species can be selectively stimulated for binding that should also carry out the implant integration after implantation in natural tissue. So it is z. B. in osteoblasts, osteoclasts and endothelial cells around α _V- carrying cell species.

The invention therefore relates to the compounds of the formula I as Integrin inhibitors for selective cell enrichment on implants.

After anchoring to a biocompatible surface as active pharmaceutical ingredients in human and Veterinary medicine can be used, especially as Integrin inhibitors for the treatment of implants Diseases, defects and inflammation such as insufficient and delayed integration of biomaterials and implants by Implants caused thrombosis, of bone and tooth defects, as well as osteolytic diseases such as osteoporosis, thrombosis, Heart attack, atherosclerosis, in wound healing to support the Healing processes, as well as to accelerate and strengthen the Integration process of the implant or the biocompatible surface into the tissue.

The compounds of formula I can act as antimicrobials Substances are used in operations where biomaterials, Implants, catheters or pacemakers can be used. They have an antiseptic effect. The effectiveness of antimicrobial Activity can be determined by the method described by P.Valentin-Weigund et al., In Infection and  Immunity, 2851-2855 (1988) become.

The invention thus relates to the compounds of the formula I as Integrin inhibitors for the treatment of implants Diseases, defects, inflammation and from osteolytic crane such as osteoporosis, thrombosis, heart attack and arteriosclerosis, as well as to accelerate and strengthen the integration process of the Implant or the biocompatible surface in the tissue.

The invention also relates to the use of compounds of formula I for the manufacture of a medicament for the treatment of by Diseases, defects, inflammation and from caused by implants osteolytic diseases such as osteoporosis, thrombosis, heart attack and atherosclerosis, as well as to accelerate and intensify the Integration process of the implant or the biocompatible surface into the tissue.

Corresponding peptides carrying thiol anchors can be covalently attached to those containing thiol Carriers such as B. implants, affinity chromatography, or microtiter plates are bound.

The invention also relates to the use of the new Compounds of formula I in affinity chromatography for elution of bound proteins.

In particular, they can be used as integrin ligands to elute integrins be used.

The abbreviations of amino acid residues listed above and below stand for the residues of the following amino acids:
Abu: 4-aminobutyric acid
Aha: 6-aminohexanoic acid, 6-aminocaproic acid
Ala: Alanine
Asn: asparagine
Asp: aspartic acid
Arg: arginine
Cys: cysteine
Dab: 2,4-diaminobutyric acid
Dap: 2,3-diaminopropionic acid
Gln: glutamine
Glp: pyroglutamic acid
Glu: glutamic acid
Gly: glycine
His: histidine
homo-Phe: homo-phenylalanine
Ile: isoleucine
Leu: Leucine
Lys: lysine
Met: methionine
Nle: norleucine
Orn: ornithine
Phe: phenylalanine
Phg: phenylglycine
4-Hal-Phe: 4-halophenylalanine
Pro: proline
Ser: Serine
Thr: Threonine
Trp: tryptophan
Tyr: tyrosine
Val: valine.

Furthermore, below mean:
Ac: acetyl
BOC: tert-butoxycarbonyl
CBZ or Z: benzyloxycarbonyl
DCCl: dicyclohexylcarbodiimide
DMF: dimethylformamide
EDCl: N-ethyl-N, N '- (dimethylaminopropyl) carbodiimide
Et: ethyl
FCA: fluorescein carboxylic acid
FITC: fluorescein isothiocyanate
Fmoc: 9-fluorenylmethoxycarbonyl
FTH: fluoresceinthiourea
HOBt: 1-hydroxybenzotriazole
Me: methyl
MBHA: 4-methyl-benzhydrylamine
Mtr: 4-methoxy-2,3,6-trimethylphenyl sulfonyl
HONSu: N-hydroxysuccinimide
OBut: tert-butyl ester
Oct: octanoyl
OMe: methyl ester
OEt: ethyl ester
POA: phenoxyacetyl
Pbf: pentamethylbenzofuranyl
Sal: salicyloyl
Su: succinyl
TFA: trifluoroacetic acid
Trt: trityl (triphenylmethyl).

Provided the above amino acids in several enantiomers Shapes can occur, are above and below, z. B. as Be Part of the compounds of formula I, all of these forms and theirs Mixtures (e.g. the DL forms) included. Furthermore, the Amino acids, e.g. B. as part of compounds of formula I with corresponding protective groups known per se.

So-called prodrug- Including derivatives, i. H. with z. B. alkyl or acyl groups, sugars or oligopeptides modified compounds of formula I, which in Organism quickly to the active compounds of the invention to be split.

This also includes biodegradable polymer derivatives of the invention appropriate connections, as z. B. in Int. J. Pharm. 115, 61-67 (1995) is described.  

The invention further relates to a process for the preparation of compounds of the formula I according to claim 1 and their salts, characterized in that

• (a) for the preparation of compounds of the formula I,
  wherein
  Q is absent, - [CO-R ¹ -NH-] _m , - (CO-CH ₂ -O-CH ₂ CH ₂ -O-CH ₂ CH ₂ -NH-) _n , or - (CO-CH ₂ -O -CH ₂ CH ₂ -O-CH ₂ CH ₂ -NH-) _n - [CO-R ¹ -NH-] _m ,
  X -CO-CH = CH ₂ or -CO-C (CH ₃ ) = CH ₂
  mean,
  and R has the meaning given in claim 1,
  • i) a compound of formula II
    RH II
    wherein
    R has the meaning given in claim 1,
    with a compound of formula III
    LQX III
    wherein
    Q is absent, - [CO-R ¹ -NH-] _m , - (CO-CH ₂ -O-CH ₂ CH ₂ -O-CH ₂ CH ₂ -NH-) _n , or - (CO-CH ₂ -O -CH ₂ CH ₂ -O-CH ₂ CH ₂ -NH-) _n - [CO-R ¹ -NH-] _m ,
    X -CO-CH = CH or -CO-C (CH ₃ ) = CH ₂
    mean,
    and
    L denotes Cl, Br, I or a free or reactively functionally modified OH group,
    implements
    or
  • ii) a compound of formula IV
    RQH IV
    wherein
    Q is absent, - [CO-R ¹ -NH-] _m or - (CO-CH ₂ -O-CH ₂ CH ₂ -O-CH ₂ CH ₂ -NH-) _n or - (CO-CH ₂ -O- CH ₂ CH ₂ -O-CH ₂ CH ₂ -NH-) _n - [CO-R ¹ -NH-] _m ,
    means and
    R has the meaning given in claim 1,
    with a compound of formula V
    LX V
    wherein
    X denotes -CO-CH = CH ₂ or -CO-C (CH ₃ ) = CH ₂ , and
    L denotes Cl, Br, I or a free or reactively functionally modified OH group,
    implements
  or
• (b) for the preparation of compounds of the formula I,
  wherein
  Q is missing, - [NH-R ¹ -CO-] _m , - [CO-R ¹ -CO-] _m or - (NH-CH ₂ -O-CH ₂ CH ₂ -O-CH ₂ CH ₂ -CO- ) _n ,
  X -NH-CH = CH ₂ , -NH-C (CH ₃ ) = CH ₂ or NH- (CH ₂ ) _p -SR ¹⁰ ,
  R ^{10 is} an S protecting group
  mean,
  and R has the meaning given in claim 1,
  • i) a compound of formula VI
    RL VI
    wherein
    L denotes Cl, Br, I or a free or reactively functionally modified OH group,
    and R has the meaning given in claim 1,
    with a compound of formula VII
    HQX VII
    wherein
    Q is absent, - [NH-R ¹ -CO-] _m or - (NH-CH ₂ -O-CH ₂ CH ₂ -O-CH ₂ CH ₂ -CO-) _n ,
    X -NH-CH = CH ₂ , -NH-C (CH ₃ ) = CH ₂ or -NH- (CH ₂ ) _p -SR ¹⁰ ,
    R ^{10 is} an S protecting group
    mean,
    implements
    or
  • ii) a compound of formula VIII
    RQL VIII
    wherein
    Q is absent, [NH-R ¹ -CO-] _m , - [CO-R ¹ -CO-] _m or (NH-CH ₂ -O-CH ₂ CH ₂ -O-CH ₂ CH ₂ -CO-) _n ,
    L denotes Cl, Br, I or a free or reactively functionally modified OH group,
    and R has the meaning given in claim 1,
    with a compound of formula IX
    HX IX
    wherein
    X -NH-CH = CH ₂ , -NH-C (CH ₃ ) = CH ₂ or -NH- (CH ₂ ) _p -SR ¹⁰ ,
    R ^{10 is} an S protecting group
    mean,
    implements
  or
• c) that they are liberated from one of their functional derivatives by treatment with a solvolysing or hydrogenolysing agent,
  and / or that a basic or acidic compound of the formula I is converted into one of its salts by treatment with an acid or base.

Above and below, the radicals R, Q, X and L have the same formulas I II, III, IV, V, VI, VII, VIII and IX meanings, if not expressly stated otherwise.

In the above formulas, alkyl preferably represents methyl, ethyl, Propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, also for Pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1- Ethyl propyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl.  

R ¹ denotes R ² , R ⁹ , R ² -R ⁹ -R ² , unsubstituted or mono- or disubstituted by R ⁵ phenylene, the chain length of R ^{5 being} independent of each other, or R ¹ is absent; in particular R ¹ denotes alkylene with 1-10 C atoms.

Alkylene preferably means methylene, ethylene, propylene, butylene, pentylene or hexylene, also heptylene, octylene, nonylene or decylene. Alkylenephenyl is preferably benzyl or phenethyl. Alkylenephenylalkylene is preferably 4-methylenebenzyl or 4- Ethylbenzyl.

Q preferably means z. B. the 6-aminohexanoic acid (6-amino caproic acid) residue, the succinyl residue, the - (CO-CH ₂ -O-CH ₂ CH ₂ -O-CH ₂ CH ₂ -NH) -, the - (CO-CH ₂ -O-CH ₂ CH ₂ -O-CH ₂ CH ₂ -NH -) - CO- (CH ₂ ) ₅ -NH- or den - (CO-CH ₂ -O-CH ₂ CH ₂ -O-CH ₂ CH ₂ -NH-) ₂ -CO- (CH ₂ ) ₅ -NH residue.

M preferably means Dap, Ser, Cys, Asp, D-Asp, Dab, homoserine, Homocysteine, Glu, D-Glu, Thr, Orn, Lys, D-Lys, 4-Aminomethyl-Phe or 4-aminomethyl-D-Phe.

The amino acids and amino acid residues mentioned in the meanings for Z can also be derivatized, the N-methyl, N-ethyl, N-propyl, N-benzyl or C _α -methyl derivatives being preferred. Also preferred are derivatives of Asp and Glu, especially the methyl, ethyl, propyl, butyl, tert-butyl. Neopentyl or benzyl esters of the side chains carboxy groups, also derivatives of Arg, which may be substituted on the -NH-C (= NH) -NH ₂ group with an acetyl, benzoyl, methoxycarbonyl or ethoxycarbonyl radical.

Z is preferably M, more preferably homo-Phe-M, phenylglycine, D-Phe-M, D-Trp-M, D-Tyr-M, D-Phe-Lys, D-Phe-D-Lys, D-Trp-Lys, D-Trp-D-Lys, DJyr-Lys, D-Tyr-D-Lys, D-Phe-Orn, D-Phe-Dab, D-Phe-Dap, D-Phe-D-Orn, D-Phe-D-Dab, D-Phe-D-Dap, D-Phe-4-aminomethyl-Phe, D-Phe-4-aminomethyl-D-Phe, D-Trp-4-aminomethyl-Phe, D-Trp-4-aminomethyl-D-Phe, D-Tyr-4-aminomethyl-Phe,  D-Tyr-4-aminomethyl-D-Phe, D-Phe-Asp, D-Phe-D-Asp, D-Trp-Asp, D-Trp-D-Asp, D-Tyr-Asp, D-Tyr-D-Asp, D-Phe-Cys, D-Phe-D-Cys, D-Trp-Cys, D-Trp-D-Cys, D-Tyr-Cys, D-Tyr-D-Cys, Phe-D-Lys, Trp-D-Lys, Tyr-D-Lys, Phe-Orn, Phe-Dab, Phe-Dap, Trp-Orn, Trp-Dab, Trp-Dap, Tyr-Orn, Tyr-Dab, Tyr-Dap, Phe-4-Aminomethyl-D-Phe, Trp4-aminomethyl-D-Phe, Tyr-4-aminomethyl-D-Phe, Phe-D-Asp, Trp-D-Asp, Tyr-D-Asp, Phe-D-Cys, Trp-D-Cys, Tyr-D-Cys, Phg-M, D-Phe-Lys-Gly, D-Phe-M-Gly, D-Trp-Lys-Gly, D-Trp-M-Gly, D-Tyr-Lys-Gly, D-Tyr-M-Gly, D-Phe-Val-Lys, D-Phe-Gly-Lys, D-Phe-Ala-Lys, D-Phe-Ile-Lys, D-Phe-Leu-Lys, D-Trp-Val-Lys, D-Trp-Gly-Lys, D-Trp-Ala-Lys, D-Trp-Ile-Lys, D-Trp-Leu-Lys, D-Tyr-Val-Lys, D-Tyr-Gly-Lys, D-Tyr-Ala-Lys, D-Tyr-Ile-Lys, D-Tyr-Leu-Lys.

The radical -R ⁶ -R ⁴ preferably denotes 2-, 3- or 4-hydroxybenzyl, 2-, 3- or 4-aminobenzyl, 2-, 3- or 4-mercaptobenzyl, 2-, 3- or 4-carboxybenzyl , further preferably 2-, 3- or 4-hydroxyphenethyl, 2-, 3- or 4-aminophenethyl, 2-, 3- or 4-mercaptophenethyl, 2-, 3- or 4-carboxyphenethyl.

Cycloalkylene preferably means cyclopropylene, 1,2- or 1,3-cyclo butylene, 1,2- or 1,3-cyclopentylene, 1,2-, 1,3- or 1,4-cyclohexylene, also 1,2-, 1,3- or 1,4-cycloheptylene.

R ^{10 represents} H or an S protecting group, such as. B. Trityl.

Amino protecting group preferably means acetyl, propionyl, butyryl, Phenylacetyl, benzoyl, toluyl, POA, methoxycarbonyl, ethoxycarbonyl, 2,2,2-chloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl, CBZ ("Carbo benzoxy "), 4-methoxybenzyloxycarbonyl, FMOC, Mtr or benzyl.

Hal is preferably F, Cl or Br, but also I.

The compounds of formula I can have one or more chiral centers possess and therefore occur in different stereoisomeric forms. Formula I encompasses all of these forms.  

Accordingly, the invention relates in particular to those compounds of the formula I in which at least one of the said radicals has one of the preferred meanings indicated above. Some preferred groups of compounds can be expressed by the following sub-formulas Ia to If, which correspond to the formula I and in which the radicals not specified have the meaning given for the formula I, but in which
in a)
D-Phe-M, Phe-M, D-Trp-M, Trp-M, D-Tyr-M, Tyr-M, D-Phg-M, Phg-M, D-Homo-Phe-M, Homo- Phe-M or D-Phe-Lys-Gly means;
in b)
Z D-Phe-M, Phe-M, D-Trp-M, Trp-M, D-Tyr-M, Tyr-M, D-Phg-M, Phg-M, D-Homo-Phe-M, Homo -Phe-M or D-Phe-Lys-Gly,
X is -CO-CH = CH ₂ , -NH-CH = CH ₂ , or -NH- (CH ₂ ) _p -SH;
in c)
Z D-Phe-M, Phe-M, D-Trp-M, Trp-M, D-Tyr-M, Tyr-M, D-Phg-M, Phg-M, D-Homo-Phe-M, Homo -Phe-M or D-Phe-Lys-Gly,
X represents -CO-CH = CH ₂ or -NH- (CH ₂ ) _p -SH;
in d)
Z D-Phe-M, Phe-M, D-Trp-M, Trp-M, D-Tyr-M, Tyr-M, D-Phg-M, Phg-M, D-Homo-Phe-M, Homo -Phe-M or D-Phe-Lys-Gly,
X -CO-CH = CH ₂ , -NH-CH = CH ₂ or -NH- (CH ₂ ) _p -SH R ¹ R ² ,
mean;
in e)
R cyclo- (Arg-Gly-Asp-D-Phe-M) or D-Phe-Lys-Gly,
X represents -CO-CH = CH ₂ , -NH-CH = CH ₂ or -NH- (CH ₂ ) _p -SH;
in f)
R cyclo- (Arg-Gly-Asp-D-Phe-M) or D-Phe-Lys-Gly,
Q -CO- (CH ₂ ) ₆ -NH, -CO- (CH ₂ ) ₂ -CO-, -CO-CH ₂ -O-CH ₂ CH ₂ -O-CH ₂ CH ₂ -NH- or - (CO -CH ₂ -O-CH ₂ CH ₂ -O-CH ₂ CH ₂ -NH-) ₂ -CO- (CH ₂ ) ₆ ,
X -CO-CH = CH ₂ , -NH-CH = CH ₂ or -NH- (CH ₂ ) _p -SH,
R ¹ R ² ,
mean.

The compounds of formula I and also the starting materials for their manufacture position are otherwise produced by methods known per se, as described in literature (e.g. in standard works such as Houben-Weyl, Methods of organic chemistry, Georg-Thieme-Verlag, Stuttgart;) are described, namely under reaction conditions for the ge mentioned implementations are known and suitable. You can also do that use of known variants not mentioned here do.

If desired, the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture, but immediately further reacted to the compounds of formula I.

Compounds of formula I can preferably be obtained by reacting compounds of formula II with compounds of formula III.

The compounds of the formula II and III are generally known. They are not known, they can be prepared by methods known per se become.

In the compounds of the formula III, the radical L is preferably one preactivated carboxylic acid, preferably a carboxylic acid halide, sym metric or mixed anhydride or an active ester. Such Residues for activation of the carboxy group in typical acylation reactions cations are in the literature (e.g. in standard works such as Houben-Weyl, Methods of organic chemistry, Georg-Thieme-Verlag, Stuttgart;) described.  

Activated esters are conveniently formed in situ, e.g. B. by addition from HOBt or N-hydroxysuccinimide.

L is preferably H, F, Cl, Br or -ON succinimide.

The reaction is usually carried out in an inert solvent Presence of an acid-binding agent, preferably an organic one Base such as triethylamine, dimethylaniline, pyridine or quinoline or one Excess of the carboxy component of formula III.

Also the addition of an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate or other salt of a weak acid Alkali or alkaline earth metals, preferably of potassium, sodium, Calcium or cesium can be beneficial.

The response time is between depending on the conditions used a few minutes and 14 days, the reaction temperature between about -30 ° and 140 °, usually between -10 ° and 90 °, in particular between about 0 ° and about 70 °.

Suitable inert solvents are, for. B. hydrocarbons such as hexane, Petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as Trichlorethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or Dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers such as diethyl ether, diisopropyl ether, Tetrahydrofuran (THF) or dioxane; Glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), Ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide or dimethylformamide (DMF); Nitriles such as acetonitrile; Sulfoxides such as dimethyl sulfoxide (DMSO); Sulfur carbon; Carboxylic acids such as formic acid or acetic acid; Nitrover bonds such as nitromethane or nitrobenzene; Esters such as ethyl acetate, Water or mixtures of the solvents mentioned.

Compounds of formula I can also be obtained by Reacts compounds of formula IV with compounds of formula V. The starting compounds of formula IV and V are usually known. If they are not known, they can be known Methods are made.  

In the compounds of the formula V, the radical L is preferably one preactivated carboxylic acid, preferably a carboxylic acid halide, symmetrical or mixed anhydride or an active ester. Such Residues for activation of the carboxy group in typical acylation reactions cations are in the literature (e.g. in standard works such as Houben-Weyl, Methods of organic chemistry, Georg-Thieme-Verlag, Stuttgart;) described.

L is preferably F, Cl, Br or -ON succinimide.

The reaction of the compounds of formula IV with compounds of Formula V takes place under the same conditions regarding the reak tion time, temperature and solvent, such as this for the implementation of the Compounds of formula II described with compounds of formula III is.

Compounds of formula I can also be obtained by Reacts compounds of formula VI with compounds of formula VII. The starting compounds of the formulas VI and VII are generally known. If they are not known, they can be known Methods are made.

In the compounds of the formula VI, the radical L preferably denotes a preactivated carboxylic acid, preferably a carboxylic acid halide, symmetrical or mixed anhydride or an active ester. Such Residues for activation of the carboxy group in typical acylation reactions cations are in the literature (e.g. in standard works such as Houben-Weyl, Methods of organic chemistry, Georg-Thieme-Verlag, Stuttgart;) described.

L is preferably F, Cl, Br or -ON succinimide.

The reaction of the compounds of formula VI with compounds of Formula VII takes place under the same conditions regarding the Reak tion time, temperature and solvent, such as this for the implementation of the Compounds of formula II described with compounds of formula III is.  

Compounds of formula I can also be obtained by Reacts compounds of formula VIII with compounds of formula IX. The starting compounds of the formulas VIII and IX are generally known. If they are not known, they can be known Methods are made.

In the compounds of formula VIII, the radical L is preferably a preactivated carboxylic acid, preferably a carboxylic acid halide, symmetrical or mixed anhydride or an active ester. Such Residues for activation of the carboxy group in typical acylation reactions cations are in the literature (e.g. in standard works such as Houben-Weyl, Methods of organic chemistry, Georg-Thieme-Verlag, Stuttgart;) described.

L is preferably F, Cl, Br or -ON succinimide.

The reaction of the compounds of formula VIII with compounds of Formula IX takes place under the same conditions regarding the Reak tion time, temperature and solvent, such as this for the implementation of the Compounds of formula II described with compounds of formula III is.

Cyclic compounds of formula II can by cyclization of the linear connections are made, such as. B. in DE 43 10 643, in Houben-Weyl, l.c., volume 15 / II, pages 1 to 806 (1974) or from S. Zimmer, E. Hoffmann, G. Jung and H. Kessler, Liebigs Ann. Chem. 1993, 497-501.

The linear peptides can e.g. B. according to R.B. Merrifield, Angew. chemistry 1985 97, 801-812.

Open chain linear connections, e.g. B. Compounds of Formula III can also by the usual methods of amino acid and Peptide synthesis are prepared, e.g. B. even after the solid phases synthesis according to Meinfield (see also e.g. F. F. Gysin and R. B. Merrifield, J. At the. Chem. Soc. 94, 3102ff. (1972)).  

The compounds of the formula I can also be obtained by to get them from their functional derivatives by solvolysis, in particular Hydrolysis, or released by hydrogenolysis.

Preferred starting materials for solvolysis or hydrogenolysis are those which, instead of one or more free amino and / or hydroxyl groups, contain corresponding protected amino and / or hydroxyl groups, preferably those which, instead of an H atom, have an N atom is connected to carry an amino protecting group, e.g. B. those which correspond to the formula I, but instead of an NH ₂ group contain an NHR 'group (in which R' is an amino protecting group, for example BOC or CBZ).

Preference is furthermore given to starting materials which instead of the H atom Hydroxy group carry a hydroxy protecting group, e.g. B. those that the Correspond to formula I, but instead of a hydroxyphenyl group an R''O- contain phenyl group (wherein R '' represents a hydroxy protecting group).

Several - identical or different - protected amino and / or hydroxyl groups present in the molecule of the starting material his. If the existing protecting groups are different from each other, they can be split off selectively in many cases.

The term "amino protecting group" is well known and refers to on groups that are suitable, an amino group before chemical order to protect (block) settlements that are easily removable, after the desired chemical reaction elsewhere in the Molecule has been carried out. Typical of such groups are ins special unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino protecting groups according to the desired Reaction (or sequence of reactions) to be removed is their type and size the rest not critical; however, preference is given to those with 1-20, in particular special 1-8 carbon atoms. The term "acyl group" is related with the present procedure in the broadest sense. He around includes aliphatic, araliphatic, aromatic or hetero cyclic carboxylic acids or sulfonic acid derived acyl groups  and in particular alkoxycarbonyl, aryloxycarbonyl and especially Aralkoxycarbonyl groups. Examples of such acyl groups are Alkanoyl such as acetyl, propionyl, butyryl; Aralkanoyl such as phenylacetyl; Aroyl such as benzoyl or toluyl; Aryloxyalkanoyl such as POA; Alkoxycarbonyl like Methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2- Iodoethoxycarbonyl; Aralkyloxycarbonyl such as CBZ ("carbobenzoxy"), 4- Methoxybenzyloxycarbonyl, FMOC; Arylsulfonyl such as Mtr. Preferred Amino protecting groups are BOC and Mtr, also CBZ, Fmoc, Benzyl and Acetyl.

The term "hydroxy protecting group" is also well known and refers to groups that are suitable for a hydroxy group protect chemical reactions that are easily removable, after the desired chemical reaction elsewhere in the Molecule has been carried out. They are typical of such groups unsubstituted or substituted aryl, aralkyl or Acyl groups, also alkyl groups. The nature and size of the hydroxy Protecting groups are not critical as they are chemical-based Reaction or sequence of reactions are removed again; are preferred Groups with 1-20, especially 1-10 carbon atoms. Examples of hydroxy protecting groups are a. Benzyl, p-nitrobenzoyl, p-toluenesulfonyl, tert.- Butyl and acetyl, with benzyl and tert-butyl being particularly preferred. The COOH groups in aspartic acid and glutamic acid are before protected in the form of their tert-butyl esters (e.g. Asp (OBut)).

The liberation of the compounds of formula I from their functional len derivatives succeed - depending on the protective group used - e.g. B. with strong acids, suitably with TFA or perchloric acid, but also with other strong inorganic acids such as hydrochloric acid or sulfur acid, strong organic carboxylic acids such as trichloroacetic acid or Sulfonic acids such as benzene or p-toluenesulfonic acid. The presence an additional inert solvent is possible, but not always required. Suitable inert solvents are preferably organic, for example carboxylic acids such as acetic acid, ethers such as Tetrahydrofuran or dioxane, amides such as DMF, halogenated carbons Hydrogen such as dichloromethane, also alcohols such as methanol,  Ethanol or isopropanol, as well as water. There are also mixtures of aforementioned solvents in question. TFA is preferred in over shot used without the addition of another solvent, perchlor acid in the form of a mixture of acetic acid and 70% perchlorine acid in the ratio 9: 1. The reaction temperatures for the cleavage are expediently between about = and about 50 °, preferably working one between 15 and 30 ° (room temperature).

The groups BOC, OBut and Mtr can e.g. B. preferably with TFA in Di chloromethane or with about 3 to 5N HCl in dioxane at 15-30 ° be the FMOC group with an approximately 5 to 50% solution of Dimethylamine, diethylamine or piperidine in DMF at 15-30 °.

The trityl group is used to protect the amino acids histidine, asparagine, Glutamine and cysteine are used. The separation takes place depending on desired end product, with TFA / 10% thiophenol, the trityl group is split off from all the amino acids mentioned, when used of TFA / anisole or TFA / thioanisole only the trityl group of His, Asn and Gln split off, whereas it remains on the Cys side chain. The Pbf (pentamethylbenzofuranyl) group is used to protect Arg used. The splitting takes place z. B. with TFA in dichloromethane.

Hydrogenolytically removable protective groups (e.g. CBZ or benzyl) can e.g. B. by treatment with hydrogen in the presence of a kata lysators (z. B. a noble metal catalyst such as palladium, appropriate on a carrier such as coal). As a solvent are the above, especially z. B. alcohols such as Methanol or ethanol 'or amides such as DMF. The hydrogenolysis is in usually at temperatures between about 0 and 100 ° and printing between about 1 and 200 bar, preferably at 20-30 ° and 1-10 bar guided. Hydrogenolysis of the CBZ group succeeds e.g. B. good at 5 to 10 % Pd / C in methanol or with ammonium formate (instead of Hydrogen) on Pd / C in methanol / DMF at 20-30 °.

A base of formula I can with an acid in the associated acid addition salt can be transferred, for example by reaction equi  valent amounts of the base and the acid in an inert solvent such as ethanol and subsequent evaporation. For this implementation In particular acids are considered, the physiologically harmless Deliver salts. So inorganic acids can be used, e.g. B. Sulfuric acid, nitric acid, hydrohalic acids such as chlorwas hydrochloric acid or hydrobromic acid, phosphoric acids such as ortho phosphoric acid, sulfamic acid, also organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, e.g. B. Formic acid, acetic acid, propionic acid, pivalic acid, diethyl acetic acid, Malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, Lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, Ascor bic acid, nicotinic acid, isonicotinic acid, methane or ethanesulfonic acid, Ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p- Toluenesulfonic acid, naphthalene mono- and disulfonic acids, lauryl sulfur acid. Salts with physiologically unacceptable acids, e.g. B. picrates, can be used to isolate and / or purify the compounds of the Formula I can be used.

On the other hand, an acid of the formula I can be reacted with a Base in one of their physiologically harmless metal or ammonium salts are transferred. The salts in particular come from Sodium, potassium, magnesium, calcium and ammonium salts in Be traditional, further substituted ammonium salts, for. B. the dimethyl, diethyl or diisopropyl ammonium salts, monoethanol, diethanol or diiso propylammonium salts, cyclohexyl, dicyclohexylammonium salts, Di benzylethylenediammonium salts, further z. B. salts with arginine or Lysine.

All temperatures above and below are given in ° C. In the The following examples mean "customary workup": If there is required to add water, if necessary, depending on the constitution of the End product to pH between 2 and 10, extracted with ethyl acetate or dichloromethane, separates, the organic phase dries over Sodium sulfate, evaporates and purifies by chromatography on silica gel  and / or by crystallization. Rf values on silica gel; Solvent: Ethyl acetate / methanol 9: 1.

RZ = retention time (minutes) with HPLC in the following systems:

[A]
Column: YMC ODS A RP 5C ₁₈ , 250 × 4.6 mm
Eluent A: 0.1% TFA in water
Eluent B: 0.1% TFA in acetonitrile
Flow: 1 ml / min
Gradient: 0-50% B / 30 min.

[B]
as a];
Gradient: 5-50% B / 30 min.

[C]
as a];
Gradient: 10-50% B / 30 min.

Mass spectrometry (MS):
El (electron impact ionization) M⁺
FAB (Fast Atom Bombardment) (M + H) ⁺

DM PP resin stands for 4- (2 ', 4'-dimethoxyphenyl-hydroxymethyl) phenoxy- Resin, which, for. B. the synthesis of side-chain protected peptides allowed.

example 1

• a) To a solution of 0.1 mmol cyclo- (Arg (Pbf) -Gly-Asp (OBut) -D- Phe-Lys) ("A") [obtainable by cyclization of H-Arg (Pbf) -Gly- Asp (OBut) -D-Phe-Lys (Z) -OH to cyclo- (Arg (Pbf) -Gly-Asp (OBut) -D-Phe-Lys (Z)) and selective cleavage of the Z group by hydrogenolysis] 0.2 mmol of succinic anhydride are added to 5 ml of DMF.
  The mixture is stirred for 5 hours at room temperature and, after customary working up, cyclo- (Arg (Pbf) -Gly-Asp (OBut) -D-Phe-Lys (N ^ε -Su)) ("B") is obtained.
• b) 1 equivalent of cysteamine hydrochloride and 1 equivalent of triphenyl methanol are dissolved in glacial acetic acid at 60 ° and 1.1 equivalent of BF ₃ etherate is added with stirring. The mixture is stirred for one hour, worked up as usual and Trt-cysteamine hydrochloride ("C") is obtained.
  By reacting "B" with "C" in dichloromethane with the addition of EDCl hydrochloride, cyclo (Arg (Pbf) - Gly-Asp (OBut) -D-Phe-Lys (NE-CO-CH ₂ CH ₂ CO-NH-CH ₂ CH ₂ -S-Trf)).
  After removal of the protective groups, cyclo- (Arg-Gly-Asp-D-Phe-Lys (N ^ε CO-CH ₂ CH ₂ CO-NH-CH ₂ CH ₂ -SH)) is obtained; RZ [B] 18.3; FAB 763.
  Analogously, by reacting "C" with cyclo- (Arg (Pbf) -Gly-Asp (OBut) -D-Phe-Lys (N ^ε Su) -Gly) and splitting off the protective groups, the compound cyclo- (Arg-Gly -Asp-D-Phe-Lys (N ^ε -CO-CH ₂ CH ₂ CO-NH-CH ₂ CH ₂ -SH) -Gly).

Example 2

• a) To a suspension of 10 mmol 6-aminohexanoic acid and 1.8 equi valent calcium hydroxide in water is given at 00 1.2 equivalents Acrylic acid chloride. It is filtered and, after the usual work-up, 6- Acrylamidohexanoic acid ("D").
• b) A solution of 10 mmol "D" and 1 equivalent of N-hydroxysuccinimide in 50 ml dichloromethane at 0 ° with 1.2 equivalents of EDCl hydrochloride added and stirred for 1 hour. Add 10 µl of glacial acetic acid, work like usual and receives 6-acrylamido-hexanoic acid (2,5-dioxopyrrolidin-1-yl) - ester ("E").
• c) By reacting "A" with "E" in DMF, cyclo (Arg (Pbf) -Gly-Asp (OBut) -D-Phe-Lys (N ^ε -CO- (CH ₂ ) ₅ ) is obtained after customary working up -NH- CO-CH = CH ₂ )).
  After removal of the protective groups, cyclo- (Arg-Gly-Asp-D-Phe-Lys (N ^ε -CO- (CH ₂ ) ₅ -NH-CO-CH = CH ₂ )) is obtained; RZ [A] 22.8; FAB 771.
  The compound cyclo- (Arg-Gly-Asp-D-Phe-Lys (N ^ε -CO- (CH ₂ ) ₅ -NH-CO-CH = CH ₂ ) -Gly) is obtained analogously.

Example 3

• a) 2 mmol of "E", dissolved in ethanol / chloroform, are added to a solution of 10 mmol of 6-aminohexanoic acid in aqueous sodium phosphate buffer (pH 8). After filtering, 6- (6-acrylamido-hexanoylamino) hexanoic acid ("F") is obtained after customary work-up.
  
• b) By reacting "A" with "F" in DMF with the addition of EDCl hydrochloride, cyclo (Arg (Pbf) -Gly-Asp (OBut) -D-Phe-Lys (N ^ε -CO - (CH ₂ ) ₅ -NH-CO- (CH ₂ ) ₅ -NH-CO-CH = CH ₂ )).
  After the protecting groups have been removed, cyclo- (Arg-Gly-Asp-D-Phe-Lys (N ^ε -CO- (CH ₂ ) ₅ -NH-CO- (CH ₂ ) ₅ -NH-CO- CH = CH ₂ )); RZ [A] 23.5; FAB 884.
  The compound cyclo- (Arg-Gly-Asp-D-Phe-Lys (N ^ε -CO- (CH ₂ ) ₅ -NH-CO- (CH ₂ ) ₅ -NH-CO-CH = CH ₂ ) is obtained analogously. -Gly).

Example 4

• a) By coupling 6-acrylamidohexanoic acid to [2- (2-aminoethoxy) ethoxy] acetic acid DMPP resin with the addition of HOBt and DCCl in dichloromethane, {2- [2- (6-acrylamidohexanoylamino) is obtained -ethoxy] - ethoxy} acetic acid DMPP resin.
  The resin is washed with CF ₃ SO ₃ H / CH ₂ Cl ₂ / H ₂ O and {2- [2- (6-acrylamido-hexanoylamino) ethoxy] ethoxy} acetic acid is obtained.
  
• b) The formation of the active ester with EDCl takes place analogously to Example 2b).
• c) By reacting the active ester with "A", the compound cyclo- (Arg (Pbf) -Gly-Asp (OBut) -D-Phe-Lys (N ^ε -CO-CH ₂ -O-CH ₂ CH ₂ - O- CH ₂ CH ₂ -NH-CO- (CH ₂ ) ₅ -NH-CO-CH = CH ₂ )).
  After the protecting groups have been removed, cyclo- (Arg-Gly-Asp-D-Phe-Lys (N ^ε -CO-CH ₂ -O-CH ₂ CH ₂ -O-CH ₂ CH ₂ -NH-CO- (CH ₂ ) ₅ -NH-CO-CH = CH ₂ )); RZ [C] 22.5; FAB 916.
  The compound cyclo- (Arg-Gly-Asp-D-Phe-Lys (N- ^ε CO- CH ₂ -O-CH ₂ CH ₂ -O-CH ₂ CH ₂ -NH-CO- (CH ₂ ) ₅ -NH-CO-CH = CH ₂ ) -Gly).
  Analogously, reaction of {2- [2- (2- {2- [2- (6-acrylamido-hexanoylamino) ethoxy] ethoxy} acetylamino) ethoxy] ethoxy] acetic acid is obtained
  with "A" the connection
  Cyclo- (Arg (Pbf) -Gly-Asp (OBut) -D-Phe-Lys (N ^ε - (CO-CH ₂ -O-CH ₂ CH ₂ -O- CH ₂ CH ₂ -NH) ₂ -CO- (CH ₂ ) ₅ -NH-CO-CH = CH ₂ )).
  After splitting off the protective groups, one obtains
  Cyclo- (Arg-Gly-Asp-D-Phe-Lys (N ^ε - (CO-CH ₂ -O-CH ₂ CH ₂ -O-CH ₂ CH ₂ -NH) ₂ - CO- (CH ₂ ) ₅ - NH-CO-CH = CH ₂ )); RZ [C] 22.75; FAB 1061.
  Cyclo- (Arg-Gly-Asp-D-Phe-Lys (N ^ε - (CO-CH ₂ -O-CH ₂ CH- O-CH ₂ CH ₂ -NH) ₂ -CO- (CH ₂ ) ₅ -NH-CO-CH = CH ₂ ) -Gly).

Example 5

Analogously to Example 1, the following ("G") cyclopeptides are obtained
Cyclo- (Arg (Pbf) -Gly-Asp (OBut) -D-Phe-Val-Lys)
Cyclo- (Arg (Pbf) -Gly-Asp (OBut) -D-Trp-Lys)
Cyclo- (Arg (Pbf) -Gly-Asp (OBut) -D-Tyr-Lys)
Cyclo- (Arg (Pbf) -Gly-Asp (OBut) -D-Phe-D-Lys)
Cyclo- (Arg (Pbf) -Gly-Asp (OBut) -D-Phe-Cys)
Cyclo- (Arg (Pbf) -Gly-Asp (OBut) -D-Phe-Dab)
Cyclo- (Arg (Pbf) -Gly-Asp (OBut) -D-Trp-D-Cys)
Cyclo- (Arg (Pbf) -Gly-Asp (OBut) -D-Tyr-D-Cys)
Cyclo- (Arg (Pbf) -Gly-Asp (OBut) -Phe-D-Lys)
Cyclo- (Arg (Pbf) -Gly-Asp (OBut) -Trp-D-Lys)
Cyclo- (Arg (Pbf) -Gly-Asp (OBut) -Tyr-D-Lys)
Cyclo- (Arg (Pbf) -Gly-Asp (OBut) -Phe-D-Cys)
Cyclo- (Arg (Pbf) -Gly-Asp (OBut) -Phe-Dab)
Cyclo- (Arg (Pbf) -Gly-Asp (OBut) -Trp-D-Cys)
Cyclo- (Arg (Pbf) -Gly-Asp (OBut) -Tyr-D-Cys)
Cyclo- (Arg (Pbf) -Gly-Asp (OBut) -D-Trp-Orn)
Cyclo- (Arg (Pbf) -Gly-Asp (OBut) -D-Tyr-Orn)
Cyclo- (Arg (Pbf) -Gly-Asp (OBut) -D-Phe-Orn)
Cyclo- (Arg (Pbf) -Gly-Asp (OBut) -D-Trp-D-Orn)
Cyclo- (Arg (Pbf) -Gly-Asp (OBut) -D-Tyr-D-Orn)
Cyclo- (Arg (Pbf) -Gly-Asp (OBut) -D-Phe-D-Orn)
Cyclo- (Arg (Pbf) -Gly-Asp (OBut) -D-Trp-Dab)
Cyclo- (Arg (Pbf) -Gly-Asp (OBut) -D-Tyr-Dab)
Cyclo- (Arg (Pbf) -Gly-Asp (OBut) -D-Trp-Dap)
Cyclo- (Arg (Pbf) -Gly-Asp (OBut) -D-Tyr-Dap)
Cyclo- (Arg (Pbf) -Gly-Asp (OBut) -D-Phe-Dap)
Cyclo- (Arg (Pbf) -Gly-Asp (OBut) -D-Trp-D-Dap)
Cyclo- (Arg (Pbf) -Gly-Asp (OBut) -D-Tyr-D-Dap)
Cyclo- (Arg (Pbf) -Gly-Asp (OBut) -D-Phe-D-Dap)
with a) succinic anhydride, b) "C" and c) removal of the protective groups, the following compounds
Cyclo- (Arg-Gly-Asp-D-Phe-Val-Lys (N ^ε -CO-CH ₂ CH ₂ CO-NH-CH ₂ CH ₂ -SH))
Cyclo- (Arg-Gly-Asp-D-Trp-Lys (N ^ε -CO-CH ₂ CH ₂ CO-NH-CH ₂ CH ₂ -SH))
Cyclo- (Arg-Gly-Asp-D-Tyr-Lys (N ^ε -CO-CH ₂ CH ₂ CO-NH-CH ₂ CH ₂ -SH))
Cyclo- (Arg-Gly-Asp-D-Phe-D-Lys (N ^ε -CO-CH ₂ CH ₂ CO-NH-CH ₂ CH ₂ -SH))
Cyclo- (Arg-Gly-Asp-D-Phe-Cys (S-CO-CH ₂ CH ₂ CO-NH-CH ₂ CH ₂ -SH))
Cyclo- (Arg-Gly-Asp-D-Phe-Dab (N ^γ -CO-CH ₂ CH ₂ CO-NH-CH ₂ CH ₂ -SH))
Cyclo- (Arg-Gly-Asp-D-Trp-D-Cys (S-CO-CH ₂ CH ₂ CO-NH-CH ₂ CH ₂ -SH))
Cyclo- (Arg-Gly-Asp-D-Tyr-D-Cys (S-CO-CH ₂ CH ₂ CO-NH-CH ₂ CH ₂ -SH))
Cyclo- (Arg-Gly-Asp-Phe-D-Lys (N ^ε -CO-CH ₂ CH ₂ CO-NH-CH ₂ CH ₂ -SH))
Cyclo- (Arg-Gly-Asp-Trp-D-Lys (N ^ε -CO-CH ₂ CH ₂ CO-NH-CH ₂ CH ₂ -SH))
Cyclo- (Arg-Gly-Asp-Tyr-D-Lys (N ^ε -CO-CH ₂ CH ₂ CO-NH-CH ₂ CH ₂ -SH))
Cyclo- (Arg-Gly-Asp-Phe-D-Cys (S-CO-CH ₂ CH ₂ CO-NH-CH ₂ CH ₂ -SH))
Cyclo- (Arg-Gly-Asp-Phe-Dab (N ^γ -CO-CH ₂ CH ₂ CO-NH-CH ₂ CH ₂ -SH))
Cyclo- (Arg-Gly-Asp-Trp-D-Cys (S-CO-CH ₂ CH ₂ CO-NH-CH ₂ CH ₂ -SH))
Cyclo- (Arg-Gly-Asp-Tyr-D-Cys (S-CO-CH ₂ CH ₂ CO-NH-CH ₂ CH ₂ -SH))
Cyclo- (Arg-Gly-Asp-D-Trp-Orn (N ^δ -CO-CH ₂ CH ₂ CO-NH-CH ₂ CH-SH))
Cyclo- (Arg-Gly-Asp-D-Tyr-Orn (N ^δ -CO-CH ₂ CH ₂ CO-NH-CH ₂ CH ₂ -SH))
Cyclo- (Arg-Gly-Asp-D-Phe-Orn (N ^δ -CO-CH ₂ CH ₂ CO-NH-CH ₂ CH ₂ -SH))
Cyclo- (Arg-Gly-Asp-D-Trp-D-Orn (N ^δ -CO-CH ₂ CH ₂ CO-NH-CH ₂ CH ₂ -SH))
Cyclo- (Arg-Gly-Asp-D-Tyr-D-Orn (N ^δ -CO-CH ₂ CH ₂ CO-NH-CH ₂ CH ₂ -SH))
Cyclo- (Arg-Gly-Asp-D-Phe-D-Orn (N ^δ -CO-CH ₂ CH ₂ CO-NH-CH ₂ CH ₂ -SH))
Cyclo- (Arg-Gly-Asp-D-Trp-Dab (N ^γ -CO-CH ₂ CH ₂ CO-NH-CH ₂ CH ₂ -SH))
Cyclo- (Arg-Gly-Asp-D-Tyr-Dab (N ^γ -CO-CH ₂ CH ₂ CO-NH-CH ₂ CH ₂ -SH))
Cyclo- (Arg-Gly-Asp-D-Trp-Dap (N ^β -CO-CH ₂ CH ₂ CO-NH-CH ₂ CH ₂ -SH))
Cyclo- (Arg-Gly-Asp-D-Tyr-Dap (N ^β -CO-CH ₂ CH ₂ CO-NH-CH ₂ CH ₂ -SH))
Cyclo- (Arg-Gly-Asp-D-Phe-Dap (N ^β -CO-CH ₂ CH ₂ CO-NH-CH ₂ CH ₂ -SH))
Cyclo- (Arg-Gly-Asp-D-Trp-D-Dap (N ^β -CO-CH ₂ CH ₂ CO-NH-CH ₂ CH ₂ -SH))
Cyclo- (Arg-Gly-Asp-D-Tyr-D-Dap (N ^β -CO-CH ₂ CH ₂ CO-NH-CH ₂ CH ₂ -SH))
Cyclo- (Arg-Gly-Asp-D-Phe-D-Dap (N ^β -CO-CH ₂ CH ₂ CO-NH-CH ₂ CH ₂ -SH)).

Analogously to Example 2, the following compounds are obtained by reacting the "G" cyclopeptides with a) "E" and b) splitting off the protective groups
Cyclo- (Arg-Gly-Asp-D-Phe4al-Lys (N ^ε -CO- (CH ₂ ) ₅ -NH-CO-CH = CH ₂ ))
Cyclo- (Arg-Gly-Asp-D-Trp-Lys (N ^ε -CO- (CH ₂ ) ₅ -NH-CO-CH = CH ₂ ))
Cyclo- (Arg-Gly-Asp-D-Tyr-Lys (N ^ε -CO- (CH ₂ ) ₅ -NH-CO-CH = CH ₂ ))
Cyclo- (Arg-Gly-Asp-D-Phe-D-Lys (N ^ε -CO- (CH ₂ ) ₅ -NH-CO-CH = CH ₂ ))
Cyclo- (Arg-Gly-Asp-D-Phe-Cys (S-CO- (CH ₂ ) ₅ -NH-CO-CH = CH ₂ ))
Cyclo- (Arg-Gly-Asp-D-Phe-Dab (N ^γ -CO- (CH ₂ ) ₅ -NH-CO-CH = CH ₂ ))
Cyclo- (Arg-Gly-Asp-D-Trp-D-Cys (S-CO- (CH ₂ ) ₅ -NH-CO-CH = CH ₂ ))
Cyclo- (Arg-Gly-Asp-D-Tyr-D-Cys (S-CO- (CH ₂ ) ₅ -NH-CO-CH = CH ₂ ))
Cyclo- (Arg-Gly-Asp-Phe-D-Lys (N ^ε -CO- (CH ₂ ) ₅ -NH-CO-CH = CH ₂ ))
Cyclo- (Arg-Gly-Asp-Trp-D-Lys (N ^ε -CO- (CH ₂ ) ₅ -NH-CO-CH = CH ₂ ))
Cyclo- (Arg-Gly-Asp-Tyr-D-Lys (N ^ε -CO- (CH ₂ ) ₅ -NH-CO-CH = CH ₂ ))
Cyclo- (Arg-Gly-Asp-Phe-D-Cys (S-CO-CH ₂ CH ₂ CO-NH-CH ₂ CH ₂ -SH))
Cyclo- (Arg-Gly-Asp-Phe-Dab (N ^γ -CO- (CH ₂ ) ₅ -NH-CO-CH = CH ₂ ))
Cyclo- (Arg-Gly-Asp-Trp-D-Cys (S-CO- (CH ₂ ) ₅ -NH-CO-CH = CH ₂ ))
Cyclo- (Arg-Gly-Asp-Tyr-D-Cys (S-CO- (CH ₂ ) ₅ -NH-CO-CH = CH ₂ ))
Cyclo- (Arg-Gly-Asp-D-Trp-Orn (N ^δ -CO- (CH ₂ ) ₅ -NH-CO-CH = CH ₂ ))
Cyclo- (Arg-Gly-Asp-D-Tyr-Orn (N ^δ -CO- (CH ₂ ) ₅ -NH-CO-CH = CH ₂ ))
Cyclo- (Arg-Gly-Asp-D-Phe-Orn (N ^δ -CO- (CH ₂ ) ₅ -NH-CO-CH = CH ₂ ))
Cyclo- (Arg-Gly-Asp-D-Trp-D-Orn (N ^δ -CO- (CH ₂ ) ₅ -NH-CO-CH = CH ₂ ))
Cyclo- (Arg-Gly-Asp-D-Tyr-D-Orn (N ^δ -CO- (CH ₂ ) ₅ -NH-CO-CH = CH ₂ ))
Cyclo- (Arg-Gly-Asp-D-Phe-D-Orn (N- ^δ CO- (CH ₂ ) ₅ -NH-CO-CH = CH ₂ ))
Cyclo- (Arg-Gly-Asp-D-Trp-Dab (N ^γ -CO- (CH ₂ ) ₅ -NH-CO-CH = CH ₂ ))
Cyclo- (Arg-Gly-Asp-D-Tyr-Dab (N ^γ -CO- (CH ₂ ) ₅ -NH-CO-CH = CH ₂ ))
Cyclo- (Arg-Gly-Asp-D-Trp-Dap (N ^β -CO- (CH ₂ ) ₅ -NH-CO-CH = CH ₂ ))
Cyclo- (Arg-Gly-Asp-D-Tyr-Dap (N ^β -CO- (CH ₂ ) ₅ -NH-CO-CH = CH ₂ ))
Cyclo- (Arg-Gly-Asp-D-Phe-Dap (N ^β -CO- (CH ₂ ) ₅ -NH-CO-CH = CH ₂ ))
Cyclo- (Arg-Gly-Asp-D-Trp-D-Dap (N ^β -CO- (CH ₂ ) ₅ -NH-CO-CH = CH ₂ ))
Cyclo- (Arg-Gly-Asp-Djyr-D-Dap (N ^β -CO- (CH ₂ ) ₅ -NH-CO-CH = CH ₂ ))
Cyclo- (Arg-Gly-Asp-D-Phe-D-Dap (N ^β -CO- (CH ₂ ) ₅ -NH-CO-CH-CH ₂ )).

Example of cell adhesion test

Adhesion of mouse MC3T3 H1 osteoblast cultures to RGD peptide-coated material surfaces was investigated in vitro. 50,000 cells / cm ^{2 were} sown and after incubation for one hour in serum-free medium at 37 ° / 95% air humidity, the proportion of adhered cells was determined.
Cell attachment rate [%] adhered cells / seeded cells × 100

Peptide: cell attachment rate [%]

Cyclo- (Arg-Gly-Asp-D-Phe-Lys (N ^ε

-CO- (CH ₂

) ₅

-NH-CO-CH = CH ₂

)): 11.3;
Cyclo- (Arg-Gly-Asp-D-Phe-Lys (N ^ε

-CO- (CH ₂

) ₅

-NH-CO- (CH ₂

) ₅

-NH-CO- CH = CH ₂

)): 92.4;
Cyclo- (Arg-Gly-Asp-D-Phe-Lys (N ^ε

-CO-CH ₂

-O-CH ₂

CH ₂

-O-CH ₂

CH ₂

-NH-CO- (CH ₂

) ₅

-NH-CO-CH = CH ₂

)): 109.0;
Cyclo- (Arg-Gly-Asp-D-Phe-Lys (N ^ε

-CO-CH ₂

CH ₂

CO-NH-CH ₂

CH ₂

-SH)): 86.2;
Cyclo- (Arg-Gly-Asp-D-Phe-Lys (N ^ε

- (CO-CH ₂

-O-CH ₂

CH ₂

-O-CH ₂

CH ₂

-NH) ₂

- CO- (CH ₂

) ₅

-NH-CO-CH = CH ₂

)): 110.5.

Claims (9)

1. Compounds of formula I.
RQX (I)
wherein
R cyclo- (Arg-Gly-Asp-Z), where Z is attached to Q in the side chain or, if Q is absent, to X,
Q is missing, - [CO-R ¹ -NH-] _m , - [NH-R ¹ -CO-] _m , - [CO-R ¹ -CO-] _m , - (CO-CH ₂ -O-CH ₂ CH ₂ -O-CH ₂ CH ₂ -NH-) _n , - (NH-CH ₂ -O-CH ₂ CH ₂ -O-CH ₂ CH ₂ CO-) _n or (CO-CH ₂ -O-CH ₂ CH ₂ -O-CH ₂ CH ₂ -NH-) _n - [CO-R ¹ -NH-] _m ,
X -CO-CH = CH ₂ , -CO-C (CH ₃ ) = CH ₂ , -NH-CH = CH ₂ ,
-NH-C (CH ₃ ) = CH ₂ or -NH- (CH ₂ ) _p -SR ¹⁰ ,
Z each independently of one another an amino acid residue or a di- or tripeptide residue, the amino acids being selected independently of one another from a group consisting of Ala, Asn, Asp, Arg, Cys, Gln, Glu, Gly, His, Homo-Phe, Ile, Leu, Lys, Met, Phe, Phg, Pro, Ser, Thr, Trp, Tyr, Val or M,
wherein the amino acids mentioned can also be derivatized, and the amino acid residues are linked to one another in a peptide-like manner via the α-amino and α-carboxy groups, and
where M is always included,
M NH (R ⁸ ) -CH (R ³ ) -COOH,
R ¹ is absent or R ² , R ⁹ , R ² -R ⁹ -R ² , unsubstituted or mono- or disubstituted by R ⁵ phenylene, the chain length of R ^{5 being} independent of each other,
R ² alkylene with 1-10 C atoms, where 1 or 2 methylene groups can be replaced by S, -CH = CH- or -C∼C-,
R ³ -R ⁵ -R ⁴ , -R ⁶ -R ⁴ , -R ⁷ -R ⁴ ,
R ⁴ OH, NH ₂ , SH or COOH,
R ⁵ alkylene with 1-6 C atoms,
R ⁶ alkylene phenylene with 7-14 C atoms,
R ⁷ alkylenephenylalkylene with 8-15 C atoms,
R ^{8 is} H, A or alkylenephenyl with 7-12 C atoms,
R ⁹ cycloalkylene with 3-7 C atoms,
R ¹⁰ H or an S protective group,
A alkyl with 1-6 C atoms,
Hal F, Cl, Br or I,
m, n each independently of one another 0, 1, 2 or 3 and
p is 1, 2 or 3,
where, in the case of residues of optically active amino acids and amino acid derivatives, both the D and the L forms are included,
as well as their salts. 2. Compounds of formula I according to claim 1

• a) cyclo- (Arg-Gly-Asp-D-Phe-Lys (N ^ε -CO-CH ₂ CH ₂ CO-NH-CH ₂ CH ₂ - SH));
• b) cyclo- (Arg-Gly-Asp-D-Phe-Lys (N ^ε -CO-CH ₂ CH ₂ CO-NH-CH ₂ CH ₂ SH) -Gly);
• c) cyclo- (Arg-Gly-Asp-D-Phe-Lys (N ^ε -CO- (CH ₂ ) ₅ -NH-CO CH = CH ₂ ));
• d) cyclo- (Arg-Gly-Asp-D-Phe-Lys (N ^ε -CO- (CH ₂ ) ₅ -NH-CO- (CH ₂ ) ₅ - NH-CO-CH = CH ₂ ));
• e) Cyclo- (Arg-Gly-Asp-D-Phe-Lys (N ^ε -CO-CH ₂ -O-CH ₂ CH ₂ -O- CH ₂ CH ₂ -NH-CO- (CH ₂ ) ₅ -NH -CO-CH = CH ₂ ));
• f) Cyclo- (Arg-Gly-Asp-D-Phe-Lys (N ^ε - (CO-CH ₂ -O-CH ₂ CH ₂ -O- CH ₂ CH ₂ -NH) ₂ -CO- (CH ₂ ) ₅ -NH-CO-CH = CH ₂ ));

and their physiologically acceptable salts. 3. A process for the preparation of compounds of formula I according to claim 1 and their salts, characterized in that

• (a) for the preparation of compounds of the formula I,
  wherein
  Q missing, - [CO-R ¹ -NH-] _m ,
  - (CO-CH ₂ -O-CH ₂ CH ₂ -O-CH ₂ CH ₂ -NH-) _n ,
  or
  - (CO-CH ₂ -O-CH ₂ CH ₂ -O-CH ₂ CH ₂ -NH-) _n - [CO-R ¹ -NH-] _m ,
  X -CO-CH = CH ₂ or -CO-C (CH ₃ ) = CH ₂
  mean,
  and R has the meaning given in claim 1,
  • i) a compound of formula II
    RH II
    wherein
    R has the meaning given in claim 1,
    with a compound of formula III
    LQX III
    wherein
    Q is absent, - [CO-R ¹ -NH-] _m , (CO-CH ₂ -O-CH ₂ CH ₂ -O-CH ₂ CH ₂ -NH-) _n , or - (CO-CH ₂ -O- CH ₂ CH ₂ -O-CH ₂ CH ₂ -NH-) _n - [CO-R ¹ -NH-] _m ,
    X -CO-CH = CH ₂ or -CO-C (CH ₃ ) = CH ₂
    mean,
    and
    L denotes Cl, Br, I or a free or reactively functionally modified OH group,
    implements
    or
  • ii) a compound of formula IV
    RQH IV
    wherein
    Q is absent, [CO-R ¹ -NH-] _m or (CO-CH ₂ -O-CH ₂ CH ₂ O-CH ₂ CH ₂ -NH-) _n or (CO-CH ₂ -O-CH ₂ CH ₂ -O-CH ₂ CH ₂ -NH-) _n - [CO-R ¹ -NH-] _m ,
    mean and
    R has the meaning given in claim 1,
    with a compound of formula V
    LX V
    wherein
    X -CO-CH = CH ₂ or -CO-C (CH ₃ ) = CH ₂
    means
    and
    L denotes Cl, Br, I or a free or reactively functionally modified OH group,
    implements
  or
• (b) for the preparation of compounds of the formula I,
  wherein
  Q is missing, - [NH-R ¹ -CO-] _m , - [CO-R ¹ -CO-] _m or - (NH-CH ₂ -O-CH ₂ CH ₂ -O-CH ₂ CH ₂ -CO- ) _n ,
  X -NH-CH = CH ₂ , -NH-C (CH ₃ ) = CH ₂ or -NH- (CH ₂ ) _p -SR ¹⁰ ,
  R ^{10 is} an S protecting group
  mean,
  and R has the meaning given in claim 1,
  • i) a compound of formula VI
    RL VI
    wherein
    L denotes Cl, Br, I or a free or reactively functionally modified OH group,
    and R has the meaning given in claim 1,
    with a compound of formula VII
    HQX VII
    wherein
    Q is absent, - [NH-R ¹ -CO-] _m or - (NH-CH ₂ -O-CH ₂ CH ₂ -O-CH ₂ CH ₂ -CO-) _n ,
    X -NH-CH = CH ₂ , -NH-C (CH ₃ ) = CH ₂ or -NH- (CH ₂ ) _p -SR ¹⁰ ,
    R ^{10 is} an S protecting group
    mean,
    implements
    or
  • ii) a compound of formula VIII
    RQL VIII
    wherein
    Q is missing, - [NH-R ¹ -CO-] _m , - [CO-R ¹ -CO-] _m or - (NH-CH ₂ -O-CH ₂ CH ₂ -O-CH ₂ CH ₂ -CO- ) _n ,
    L denotes Cl, Br, I or a free or reactively functionally modified OH group,
    and R has the meaning given in claim 1,
    with a compound of formula IX
    HX IX
    wherein
    X -NH-CH = CH ₂ , -NH-C (CH ₃ ) = CH ₂ or NH- (CH ₂ ) _p -SR ¹⁰ ,
    R ^{10 is} an S protecting group
    mean,
    implements
  or
• c) that they are liberated from one of their functional derivatives by treatment with a solvolysing or hydrogenolysing agent,
  and / or that a basic or acidic compound of the formula I is converted into one of its salts by treatment with an acid or base.

4. Compounds of formula I according to claim 1 for covalent bonding via the functional group of the radical X to biocompatible Surfaces. 5. Compounds according to claim 4 as integrin inhibitors for selective Cell enrichment on implants. 6. Compounds according to claim 4 or 5 as integrin inhibitors for Treatment of diseases caused by implants, Defects, inflammation and osteolytic diseases such as Osteoporosis, thrombosis, heart attack and arteriosclerosis, as well as for Accelerate and strengthen the integration process of the Implant or the biocompatible surface in the tissue. 7. Use of compounds according to claim 6 for the preparation a medicine used to treat implants diseases, defects, inflammation and caused by osteolytic diseases such as osteoporosis, thrombosis, Heart attack and arteriosclerosis, as well as for acceleration and Reinforcing the integration process of the implant or the biocompatible surface in the tissue.   8. Use of compounds of formula I according to claim 1, for covalent binding to biocompatible surfaces. 9. Use of compounds of formula I according to claim 1 in the Affinity chromatography.